The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Michael R Migden - One of the best experts on this subject based on the ideXlab platform.

  • effects of Sonidegib following dose reduction and treatment interruption in patients with advanced basal cell carcinoma during 42 month bolt trial
    Dermatologic Therapy, 2021
    Co-Authors: Karl D Lewis, Alexander Guminski, Nicholas Squittieri, Reinhard Dummer, Aaron S Farberg, Michael R Migden
    Abstract:

    Introduction Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of Sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. Methods BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to Sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. Results The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving Sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving Sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). Conclusion Dose reductions and interruptions were practical and did not impact the efficacy of Sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. Trial registration ClinicalTrials.gov identifier, NCT01327053.

  • a review of hedgehog inhibitors Sonidegib and vismodegib for treatment of advanced basal cell carcinoma
    Journal of Drugs in Dermatology, 2021
    Co-Authors: Michael R Migden, Nicholas Squittieri, Reinhard Dummer, Aaron S Farberg, William C Hanke
    Abstract:

    Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) Sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for Sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between Sonidegib and vismodegib is their respective pharmacokinetic profiles with Sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of Sonidegib and vismodegib based on published literature to date. J Drugs Dermatol. 2021;20(2):156-165. doi:10.36849/JDD.5657 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

  • effects of Sonidegib dose reduction or delay in locally advanced basal cell carcinoma 42 month data from bolt
    Journal of Clinical Oncology, 2018
    Co-Authors: Karl D Lewis, Michael R Migden
    Abstract:

    9573Background: Sonidegib is a hedgehog pathway inhibitor (HPI) approved for the treatment of locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. Patient...

  • 42 month follow up of Sonidegib efficacy and safety in advanced basal cell carcinoma final analysis from bolt
    Journal of Clinical Oncology, 2018
    Co-Authors: Michael R Migden, Karl D Lewis
    Abstract:

    9551Background: Sonidegib is a hedgehog pathway inhibitor (HPI) approved in the United States for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) not amenable to ...

  • long term efficacy and safety of Sonidegib in patients with locally advanced and metastatic basal cell carcinoma 30 month analysis of the randomized phase 2 bolt study
    Journal of The European Academy of Dermatology and Venereology, 2018
    Co-Authors: John T Lear, Ralf Gutzmer, Alexander Guminski, Karl D Lewis, Anne Lynn S Chang, Michael R Migden, Luc Dirix, Patrick Combemale, A Stratigos, R Plummer
    Abstract:

    Background Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. Objective To evaluate long-term efficacy and safety of Sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. Methods BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment–naive patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to Sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. Results With 30 months of follow-up, among patients treated with Sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). Conclusion Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of Sonidegib 200 mg per local treatment guidelines.

Reinhard Dummer - One of the best experts on this subject based on the ideXlab platform.

  • assessment of various efficacy outcomes using erivance like criteria in patients with locally advanced basal cell carcinoma receiving Sonidegib results from a preplanned sensitivity analysis
    BMC Cancer, 2021
    Co-Authors: Ralf Gutzmer, Carmen Loquai, Caroline Robert, Ramon Arntz, Serena Martelli, Nicholas Squittieri, Dirk Schadendorf, Reinhard Dummer
    Abstract:

    BACKGROUND The BOLT study for Sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received Sonidegib 200 mg once daily. METHODS This phase 2, double-blind study randomized patients 1:2 to Sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. RESULTS Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). CONCLUSIONS Overall, applying ERIVANCE-like criteria to patients with laBCC receiving Sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. TRIAL REGISTRATION BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

  • effects of Sonidegib following dose reduction and treatment interruption in patients with advanced basal cell carcinoma during 42 month bolt trial
    Dermatologic Therapy, 2021
    Co-Authors: Karl D Lewis, Alexander Guminski, Nicholas Squittieri, Reinhard Dummer, Aaron S Farberg, Michael R Migden
    Abstract:

    Introduction Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of Sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. Methods BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to Sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. Results The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving Sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving Sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). Conclusion Dose reductions and interruptions were practical and did not impact the efficacy of Sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. Trial registration ClinicalTrials.gov identifier, NCT01327053.

  • a review of hedgehog inhibitors Sonidegib and vismodegib for treatment of advanced basal cell carcinoma
    Journal of Drugs in Dermatology, 2021
    Co-Authors: Michael R Migden, Nicholas Squittieri, Reinhard Dummer, Aaron S Farberg, William C Hanke
    Abstract:

    Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) Sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for Sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between Sonidegib and vismodegib is their respective pharmacokinetic profiles with Sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of Sonidegib and vismodegib based on published literature to date. J Drugs Dermatol. 2021;20(2):156-165. doi:10.36849/JDD.5657 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

  • expression of glioma associated oncogene homolog 1 as biomarker with Sonidegib in advanced basal cell carcinoma
    Oncotarget, 2020
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Nicholas Squittieri, Li Liu, John T Lear
    Abstract:

    The pivotal BOLT (Basal cell carcinoma Outcomes with LDE225 [Sonidegib] Treatment) study established the durable efficacy and manageable toxicity of Sonidegib 200 mg once daily (QD) through 42 months in patients with advanced basal cell carcinoma (BCC). This secondary analysis used expression of Glioma-associated oncogene homolog 1 (GLI1) as a biomarker to assess the extent of Hedgehog pathway inhibition by Sonidegib in patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC). The study enrolled 230 patients, 79 and 151 receiving Sonidegib 200 and 800 mg QD, respectively. At week 17, GLI1 expression was reduced from baseline by a median percentage (95% confidence interval) of 88.7% (54.6%-93.0%) and 97.0% (77.5%-98.9%) for aggressive laBCC, 97.5% (80.3%-98.8%) and 95.0% (80.7%-97.5%) for nonaggressive laBCC, and 99.1% (96.4%-99.6%) and 99.3% (95.9%-99.9%) for mBCC in the 200 and 800 mg groups, respectively. Substantial repression of GLI1 was observed in patient subgroups stratified by age, sex, BCC cytological subtype, Eastern Cooperative Oncology Group performance status, lesion site, baseline number of BCCs, and prior radiotherapy. Results support further studies on the inhibition of Hedgehog pathway genes by Sonidegib in patients with laBCC and mBCC.

  • long term efficacy and safety of Sonidegib in patients with advanced basal cell carcinoma 42 month analysis of the phase ii randomized double blind bolt study
    British Journal of Dermatology, 2020
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Karl D Lewis, John T Lear, Anne Lynn S Chang, Patrick Combemale, A Guminksi, Luc Dirix
    Abstract:

    Background: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (Sonidegib) Treatment]. Objectives: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of Sonidegib. Methods: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to Sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. Results: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. Conclusions: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support Sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (Sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed Sonidegib as a viable long-term treatment option for patients with advanced BCC.

Karl D Lewis - One of the best experts on this subject based on the ideXlab platform.

  • effects of Sonidegib following dose reduction and treatment interruption in patients with advanced basal cell carcinoma during 42 month bolt trial
    Dermatologic Therapy, 2021
    Co-Authors: Karl D Lewis, Alexander Guminski, Nicholas Squittieri, Reinhard Dummer, Aaron S Farberg, Michael R Migden
    Abstract:

    Introduction Sonidegib is a Hedgehog pathway inhibitor approved to treat locally advanced basal cell carcinoma and, depending on regulatory approval, metastatic basal cell carcinoma. Results from the BOLT study demonstrated robust efficacy and continued tolerability through 42 months. This analysis evaluated the impact of Sonidegib dose reductions and interruptions in patients with advanced basal cell carcinoma through 42 months. Methods BOLT was a randomized, double-blind, multicenter, phase 2 study. Adults with no previous Hedgehog pathway inhibitor therapy were randomized 1:2 to Sonidegib 200 or 800 mg once daily. Primary endpoint was objective response rate. Dose modifications were permitted in patients unable to tolerate the dosing schedule or if a treatment-related adverse event was suspected. Results The incidence of dose interruptions was similar between the 200- and 800-mg groups (68.4% vs 65.3%, respectively). Dose reductions occurred more frequently in patients receiving Sonidegib 800 mg (36.7%) than 200 mg (16.5%). Overall response rate for all patients receiving Sonidegib 200 mg daily was 48.1% and was similar to those of patients without dose reduction or interruption (48.5%) and patients with at least one dose reduction or interruption (46.2%). Conclusion Dose reductions and interruptions were practical and did not impact the efficacy of Sonidegib. In patients with advanced basal cell carcinoma who necessitate long-term treatment, dose interruptions may be beneficial for continued treatment and disease control. Trial registration ClinicalTrials.gov identifier, NCT01327053.

  • key clinical adverse events in patients with advanced basal cell carcinoma treated with Sonidegib or vismodegib a post hoc analysis
    Dermatologic Therapy, 2021
    Co-Authors: Ralf Gutzmer, Brigitte Dréno, Carmen Loquai, Caroline Robert, Alexander Guminski, Karl D Lewis, Ramon Arntz, Serena Martelli, Nicholas Squittieri
    Abstract:

    Introduction Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the Sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. Methods This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received Sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for Sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Results Over 18 treatment cycles, the most common all-grade AEs for Sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. Conclusion This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with Sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.

  • key clinical adverse events in patients with advanced basal cell carcinoma treated with Sonidegib or vismodegib a post hoc analysis
    Dermatologic Therapy, 2021
    Co-Authors: Ralf Gutzmer, Brigitte Dréno, Carmen Loquai, Caroline Robert, Alexander Guminski, Karl D Lewis, Ramon Arntz, Serena Martelli, Nicholas Squittieri
    Abstract:

    Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the Sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received Sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for Sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Over 18 treatment cycles, the most common all-grade AEs for Sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with Sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.

  • long term efficacy and safety of Sonidegib in patients with advanced basal cell carcinoma 42 month analysis of the phase ii randomized double blind bolt study
    British Journal of Dermatology, 2020
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Karl D Lewis, John T Lear, Anne Lynn S Chang, Patrick Combemale, A Guminksi, Luc Dirix
    Abstract:

    Background: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (Sonidegib) Treatment]. Objectives: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of Sonidegib. Methods: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to Sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. Results: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. Conclusions: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support Sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (Sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed Sonidegib as a viable long-term treatment option for patients with advanced BCC.

  • effects of Sonidegib dose reduction or delay in locally advanced basal cell carcinoma 42 month data from bolt
    Journal of Clinical Oncology, 2018
    Co-Authors: Karl D Lewis, Michael R Migden
    Abstract:

    9573Background: Sonidegib is a hedgehog pathway inhibitor (HPI) approved for the treatment of locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. Patient...

Ralf Gutzmer - One of the best experts on this subject based on the ideXlab platform.

  • assessment of various efficacy outcomes using erivance like criteria in patients with locally advanced basal cell carcinoma receiving Sonidegib results from a preplanned sensitivity analysis
    BMC Cancer, 2021
    Co-Authors: Ralf Gutzmer, Carmen Loquai, Caroline Robert, Ramon Arntz, Serena Martelli, Nicholas Squittieri, Dirk Schadendorf, Reinhard Dummer
    Abstract:

    BACKGROUND The BOLT study for Sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received Sonidegib 200 mg once daily. METHODS This phase 2, double-blind study randomized patients 1:2 to Sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. RESULTS Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3-68.3%) and 71.2% (58.7-81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8-72.4%) and 74.2% (62.0-84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). CONCLUSIONS Overall, applying ERIVANCE-like criteria to patients with laBCC receiving Sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. TRIAL REGISTRATION BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

  • key clinical adverse events in patients with advanced basal cell carcinoma treated with Sonidegib or vismodegib a post hoc analysis
    Dermatologic Therapy, 2021
    Co-Authors: Ralf Gutzmer, Brigitte Dréno, Carmen Loquai, Caroline Robert, Alexander Guminski, Karl D Lewis, Ramon Arntz, Serena Martelli, Nicholas Squittieri
    Abstract:

    Introduction Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the Sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. Methods This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received Sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for Sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Results Over 18 treatment cycles, the most common all-grade AEs for Sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. Conclusion This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with Sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.

  • key clinical adverse events in patients with advanced basal cell carcinoma treated with Sonidegib or vismodegib a post hoc analysis
    Dermatologic Therapy, 2021
    Co-Authors: Ralf Gutzmer, Brigitte Dréno, Carmen Loquai, Caroline Robert, Alexander Guminski, Karl D Lewis, Ramon Arntz, Serena Martelli, Nicholas Squittieri
    Abstract:

    Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the Sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received Sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for Sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Over 18 treatment cycles, the most common all-grade AEs for Sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with Sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.

  • expression of glioma associated oncogene homolog 1 as biomarker with Sonidegib in advanced basal cell carcinoma
    Oncotarget, 2020
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Nicholas Squittieri, Li Liu, John T Lear
    Abstract:

    The pivotal BOLT (Basal cell carcinoma Outcomes with LDE225 [Sonidegib] Treatment) study established the durable efficacy and manageable toxicity of Sonidegib 200 mg once daily (QD) through 42 months in patients with advanced basal cell carcinoma (BCC). This secondary analysis used expression of Glioma-associated oncogene homolog 1 (GLI1) as a biomarker to assess the extent of Hedgehog pathway inhibition by Sonidegib in patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC). The study enrolled 230 patients, 79 and 151 receiving Sonidegib 200 and 800 mg QD, respectively. At week 17, GLI1 expression was reduced from baseline by a median percentage (95% confidence interval) of 88.7% (54.6%-93.0%) and 97.0% (77.5%-98.9%) for aggressive laBCC, 97.5% (80.3%-98.8%) and 95.0% (80.7%-97.5%) for nonaggressive laBCC, and 99.1% (96.4%-99.6%) and 99.3% (95.9%-99.9%) for mBCC in the 200 and 800 mg groups, respectively. Substantial repression of GLI1 was observed in patient subgroups stratified by age, sex, BCC cytological subtype, Eastern Cooperative Oncology Group performance status, lesion site, baseline number of BCCs, and prior radiotherapy. Results support further studies on the inhibition of Hedgehog pathway genes by Sonidegib in patients with laBCC and mBCC.

  • Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma a joint expert opinion
    Journal of The European Academy of Dermatology and Venereology, 2020
    Co-Authors: R Dummer, Brigitte Dréno, N Bassetseguin, Ralf Gutzmer, Axel Hauschild, P A Ascierto, Claus Garbe, R Krattinger, John T Lear, J Malvehy
    Abstract:

    Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (Sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of Sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST-like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for Sonidegib according to central review at 18-month follow-up was 60.6% (95% CI: 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half-life. Further studies are needed to understand how these differences may impact clinical practice.

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  • long term efficacy and safety of Sonidegib in patients with advanced basal cell carcinoma 42 month analysis of the phase ii randomized double blind bolt study
    British Journal of Dermatology, 2020
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Karl D Lewis, John T Lear, Anne Lynn S Chang, Patrick Combemale, A Guminksi, Luc Dirix
    Abstract:

    Background: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (Sonidegib) Treatment]. Objectives: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of Sonidegib. Methods: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to Sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. Results: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. Conclusions: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support Sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (Sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed Sonidegib as a viable long-term treatment option for patients with advanced BCC.

  • long term efficacy and safety of Sonidegib in patients with locally advanced and metastatic basal cell carcinoma 30 month analysis of the randomized phase 2 bolt study
    Journal of The European Academy of Dermatology and Venereology, 2018
    Co-Authors: John T Lear, Ralf Gutzmer, Alexander Guminski, Karl D Lewis, Anne Lynn S Chang, Michael R Migden, Luc Dirix, Patrick Combemale, A Stratigos, R Plummer
    Abstract:

    Background Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. Objective To evaluate long-term efficacy and safety of Sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. Methods BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment–naive patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to Sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. Results With 30 months of follow-up, among patients treated with Sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). Conclusion Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of Sonidegib 200 mg per local treatment guidelines.

  • the 12 month analysis from basal cell carcinoma outcomes with lde225 treatment bolt a phase ii randomized double blind study of Sonidegib in patients with advanced basal cell carcinoma
    Journal of The American Academy of Dermatology, 2016
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Carmen Loquai, Alexander Guminski, Karl D Lewis, Luc Dirix, Patrick Combemale, R Herd, Martin Kaatz, A Stratigos
    Abstract:

    Background The hedgehog pathway inhibitor Sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC Outcomes with LDE225 Treatment study. Objective This report provides long-term follow-up data collected up to 12 months after the last patient was randomized. Methods In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to Sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review. Results Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with Sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). Limitations No placebo or comparator arms were used because Sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. Conclusion With longer follow-up, Sonidegib demonstrated sustained tumor responses in patients with advanced BCC.

  • efficacy and safety of Sonidegib in patients pts with locally advanced la or metastatic m basal cell carcinoma bcc bolt 30 month analysis
    Journal of Clinical Oncology, 2016
    Co-Authors: Reinhard Dummer, Ralf Gutzmer, Alexander Guminski, Karl D Lewis, Michael R Migden, Luc Dirix, Ragini R Kudchadkar, Uwe Trefzer, P Combemale, Carmen Loquai
    Abstract:

    9538Background: Sonidegib 200 mg was approved for use in pts with advanced BCC (aBCC; laBCC + mBCC) or laBCC not amenable to surgery/radiotherapy based on results from BOLT (NCT01327053). Updated d...

  • treatment with two different doses of Sonidegib in patients with locally advanced or metastatic basal cell carcinoma bolt a multicentre randomised double blind phase 2 trial
    Lancet Oncology, 2015
    Co-Authors: Michael R Migden, Ralf Gutzmer, Alexander Guminski, Karl D Lewis, Luc Dirix, Patrick Combemale, R Herd, Ragini R Kudchadkar, Uwe Trefzer, Sven Gogov
    Abstract:

    Summary Background Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of Sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. Methods BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral Sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. Findings Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg Sonidegib group, and 151 in the 800 mg Sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg Sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg Sonidegib achieved an objective response. In the 200 mg Sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. Interpretation The benefit-to-risk profile of 200 mg Sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Funding Novartis Pharmaceuticals Corporation.